The processes of blood filtration and hemoperfusion for purification of blood are well known. With few exceptions, the devices which are employed for these purposes are capable of removing substances only in a nonspecific manner. Removal of toxic or undesirable species from the blood is accomplished on the basis of molecular size, as by dialysis employing semipermeable membranes (see U.S. Pat. No. 3,619,423); on the basis of ionic nature, as by perfusion over ion-exchange resins (see U.S. Pat. Nos. 3,794,584; 4,031,010); or on the basis of affinity for adsorbents, as by perfusion over activated charcoal. These techniques exhibit severe limitations arising from lack of specificity. Within the fraction removed from the blood are hormones, nutrients, drugs, electrolytes, and other species, whose deletion from circulation may well result in adverse effects upon the perfused patient. Since patients requiring such treatment are suffering from drug overdose, renal or hepatic failure, or other conditions severely diminishing their vitality, further metabolic imbalance may be poorly tolerated. A further disadvantage of lack of specificity in hemoperfusion devices is the limited capacity for the target species. The target species must compete with other substances for the available binding sites on the adsorbent. Such devices must be inordinately large to ensure sufficient capacity for the target species.
In addition to the nonspecificity problems exhibited by these devices, further complications have arisen with respect to structure and flow properties. Damage to formed elements and macromolecular components of the blood, by hemolysis, platelet aggregation, fibrin formation, and leukocyte destruction, for example, are often observed when blood is exposed to nonbiological surfaces or to turbulent flow. Heparinizing patients is only partially effective in preventing such damage. Hemoperfusion devices incorporating randomly dispersed particulate adsorbents have shown a propensity to pack under flow conditions. The result is an excessive pressure drop and diminished flow across the device. Blood damage increases under such conditions.
Many attempts have been made to overcome these problems and to design devices that exhibit specificity and applicability and to a wider range of molecular species, in particular high-molecular-weight species. Some synthetic matrices which have been examined show specific affinity for particular solutes. One such device employs fluorocarbon plastics for the specific removal of endotoxin. (U.S. Pat. No. 3,959,128).
Further specificity has been achieved by the use of bioactive substances bound to inert organic or inorganic materials in hemoperfusion systems. Examples of this type are the following. The affinity of bilirubin and chenodeoxycholic acid for serum albumin has been exploited by several researchers. The antigen-antibody interaction has also been employed (Canadian Pat. No. 957,922). Immobilized antigens have been perfused with blood to remove antibodies to BSA, to DNA, to HSA and ovalbumin, to blood factor VIII, and to immunoglobulin fractions IgG and ImG. Immobilized antibodies (IgG IgM) have been employed in hemoperfusion systems to diminish circulating levels of drugs and endogenous species. Antibodies to digoxin, to DNA, to BSA, to tumor-associated antigens, and to donor-kidney antigens and multiple myeloma protein, and low-density lipoproteins have been immobilized in extracorporeal systems for a variety of therapeutic purposes.
Among the enzymes, cell extracts, and whole cells that have been immobilized in extracorporeal systems (Canadian Pat. No. 957,922) are urease, uricase, aspariginase, pancreatic cells, liver cells, and liver microsomes, nuclease, and catalase.
The properties of materials and devices brought into contact with circulating biological fluids have been extensively studied. Weetall et al. have listed the following criteria as a checklist in device design: "Some In Vivo and In Vitro studies of Biologically Active Molecules on Organic Matrixes for Potential Therapeutic Applications" in Biomedical Applications of Immobilized Enzymes and Proteins, T. M. S. Chang, Ed., Plenum Press, New York, N.Y. "(1) laminar flow, (2) velocity gradient should exceed 350/sec, (3) material in contact with blood should be relatively nonthrombogenic, (4) smooth surfaces should be maintained, (5) minimum flow channel diameter of about 100 .mu.m, (6) avoidance of crushing or grinding action of support material." Two further criteria are of considerable importance: (1) maximum loading of active blood altering species per unit of priming volume, and (2) minimal resistance to active contact of said species with the blood component to be altered, i.e. contact should require a minimum of diffusion-controlled transport and the transport should be through minimally resistant matter.
To date all hemoperfusion systems employing highly specific detoxifying species isolated within the device have employed one of four arrangements: (1) isolation of the detoxifying species by partitioning it from the perfusing blood, employing semipermeable membranes (e.g. U.S. Pat. No. 3,619,423) or hollow-fiber tubes; (2) encapsulation in or attachment to particulate materials (e.g. U.S. Pat. No. 3,865,726); (3) attachment of the species to a nonporous membrane or other planar surface (e.g. U.S. Pat. No. 3,959,128); or (4) attachment to the internal surface of polymeric tubes through which blood is passed (e.g. Canadian Pat. No. 957,922).
None of these systems meets all of the criteria listed above. Semipermeable membrane and hollow-fiber devices impose strong diffusion requirements for active participation of isolated elements and are limited to activity with low-molecular-weight species in the blood. Devices employing particulate components in which the active species is microencapsulated or sequestered within the pores of the support suffer from the same limitations of diffusion resistance, and additionally exhibit flow resistance due to packing, as well as blood damage arising from the grinding action of particulate movement. Nonporous planar surfaces and polymeric tubes have low surface area and thus insufficient capacity for active elements.
An alternative to these arrangements is the use of fiber-filled cartridges. Fibers have long been employed in blood contacting devices for removing aggregates of blood components during transfusion (e.g. U.S. Pat. No. 3,462,361). Polymeric fibers having pyrolytic carbon deposited on their surface and deployed in a random mass have been employed as nonspecific adsorbants in hemoperfusion (e.g. U.S. Pat. No. 3,972,818). Antibodies and other proteins have been incorporated into cellulose fibers by entrapment, for application in radioimmunoassay and for industrial use (e.g. U.S. Pat. No. 4,031,201). Antigens have been attached to nylon catheters and inserted into arteries for the removal of antibodies from the circulation.
In the art of hemoperfusion, devices designed for highly specific alteration of blood composition and containing fibers have been employed with limited success. Hersh and Weetall (supra) used a cartridge containing bio-active molecules bound to randomly dispersed, nonporous, polyester fibers. Both enzymes and antibodies have been immobilized by their technique. These devices represent a significant improvement over previous hemoperfusion systems with respect to minimizing damage to formed elements of the blood. Some problems with this design still remain however. Unanchored, randomly dispersed fibers tend to pack under the desired flow rates when sufficient fiber is available to furnish the requisite amounts of the bound active species. Furthermore, channeling (uneven distribution of flow) which is inevitable with this fiber arrangement results in diminished efficiency for the device.
Antibodies attached in a rigidly fixed 2-dimensional array have been described and employed for the removal of whole cells from blood in vitro (e.g. U.S. Pat. No. 3,843,324). This system, however, would not be applicable to hemoperfusion.
Polymeric fibers having carbon particles encapsulated within the polymer and being deployed in a nonrandom fashion within a hemoperfusion cartridge have been described by Davis et al. (Trans. Amer. Soc. Artif. Int. Org. 20:353). Although limited to application in nonspecific adsorption, this device exhibited superior properties with respect to capacity, cost, flow properties, and diminished damage to the perfusing blood.